Affiliations:Department of Child and Adolescent Psychiatry, King´s College London, Institute of Psychiatry, UK

Stimulant medication (e.g., Methylphenidate or Dexamphetamines) are first line treatment for ADHD as they reduce the severity of ADHD core symptoms in up to 70% of patients. Several brain imaging studies have sought to further our understanding on the acute and chronic effects of stimulant medications on the function, structure and brain chemistry of ADHD.

Our meta-analysis of all 14 published whole-brain fMRI studies that tested the effects of stimulants on brain function in ADHD showed that the most consistent acute effect is the increased activation of right IFC/insula, with additional effects in the putamen at a more lenient threshold (Rubia et al., 2014, see Figure 1).

Relatively little, however, is known about chronic effects of psychostimulants. Our meta-regression analyses across fMRI studies of attention and inhibition found that long-term stimulant administration (between 6 months to 3 years) was associated with normalization of right caudate activity during attention (Hart et al., 2013) and of right DLPFC activity during timing tasks (Hart et al., 2012). In conclusion, the meta-analytic findings suggest that acute and longer-term stimulant medication treatment is most consistently associated with an upregulation of two key dysfunctional areas in ADHD, the right IFC and the basal ganglia.

Unfortunately there are no prospective longitudinal imaging studies of long-term stimulant effects on brain structure. However, retrospective comparisons of medicated and non-medicated ADHD patients suggest that medicated patients with ADHD have more normal size, cortical thickness, volumes and/or morphology than unmedicated patients in ADHD-relevant brain regions including the right inferior frontal and parietal cortices, the anterior cingulate, the anterior thalamic pulvinar, the posterior inferior vermis of the cerebellum, the left lateral cerebellar surface, the basal ganglia, and the corpus callosum (for review see Rubia et al., 2014). Two meta-regression analyses of whole brain structural MRI studies tested for long-term medication effects. Both studies found that long-term stimulant medication was associated with more normal basal ganglia volumes in ADHD (Frodl et al., 2012, Nakao et al., 2011; see Figure 2).

In conclusion, overall sMRI and fMRI studies suggest that stimulant medication may potentially be neuro-protective on brain structure and function. Studies that have tested for neurochemical effects, however, have been less promising. Our meta-analysis of PET studies in mostly adult ADHD patients showed that long-term stimulant medication was associated with an abnormally increased level of striatal dopamine transporters, which were reduced relative to healthy controls in medication-naïve patients, suggesting potential brain adaptation to stimulants (Fusar-Poli et al., 2012, see Figure 3). This was also observed in 10 adults with ADHD in a within-subject study design after a one year follow-up of chronic stimulant medication treatment. These findings of plastic long-term upregulation of DAT with chronic stimulant medication could explain relatively poor long-term efficacy of stimulant medication. However, prospective longitudinal imaging studies within a randomized placebo-controlled design are crucial to confirm these findings of plastic effects based on cross-sectional comparisons on brain structure, function and neurochemistry.

Very few studies have tested brain effects of the only other licensed medication for ADHD, Atomoxetine. In a placebo-controlled randomized study, we found shared effects of Atomoxetine and Methylphenidate of upregulation of right inferior frontal cortex (IFC) activation during time discrimination and of bilateral IFC activation during inhibition, which was furthermore normalised with both drugs in their underactivation in ADHD patients under placebo relative to healthy controls (Cubillo et al., 2013a, Smith et al., 2013). Both drugs also elicited compensatory fronto-striato-thalamic overactivation in ADHD children during working memory and both drugs deactivated default mode network activation (Cubillo et al., 2013b). Drug-specific effects, however, were also observed with Atomoxetine upregulating and normalised right dorsolateral prefrontal cortex activation during working memory (Cubillo et al., 2013b) and Methylphenidate increasing compensatory activation in left IFC and the basal ganglia during response execution and one of the WM conditions (Cubillo et al., 2013a,b). Furthermore, Methylphenidate had drug-specific effects on the activation of the dopaminergically innervated SMA during motor response execution and time discrimination (Cubillo et al., 2013a, Smith et al., 2013). In conclusion, both psychostimulants and Atomoxetine appear to enhance the activation of right IFC, presumably via their shared mechanism of action on catecholamines in frontal brain regions, but they seem to also have drug-specific effects in other frontal and subcortical regions. Further studies, however, are needed to disentangle the shared and specific drug effects of Atomoxetine relative to stimulant medication on ADHD brain function.

Given that Serotonin has been found to be involved in both impulsiveness and ADHD, we also tested the effects of a serotonin reuptake inhibitor (SSRI) on the brain function of ADHD children relative to placebo in a randomised controlled design. Interestingly fluoxetine upregulated and normalised both the dorsolateral perfrontal activation during working memory and the inferior frontal activation during response inhibition (Chantiluke et al., 2014). The findings suggest that a serotonin agonist can also modulate key brain activation deficits in ADHD just like Atomoxetine and Methylphenidate and suggest that further studies need to be undertaken to assess effects of Serotonin agonists on ADHD behaviour and brain function.

In conclusion, monoamine agonists have an effect on the brain function of ADHD patients and are likely associated with the underlying brain function and structure abnormalities of the disorder. However, more PET and (f)MRI studies are needed to understand their mechanism of action and how the underlying neurotransmitter interact with each other in ADHD.

Figure 1

Stimulant medication in an acute dose most consistently upregulates the right inferior prefrontal cortex and the basal ganglia (Rubia et al., 2014).

Figure 2

Long-term stimulant medication effects on the grey matter in the basal ganglia. The higher the percentage of long-term medicated patients, the more normal the basal ganglia grey matter volumes (Nakao et al., 2011).